Bladder function is traditionally believed to be regulated, under neuromuscular control, through functional interrelationships between neural, muscular, and connective tissue components of the bladder. Dockray, GH..; Gut Peptides: Biochemistry and Physiology, Raven Press, New York, N.Y. (1994); p. 1-11, 423-445. The basic cytological aspects of bladder smooth muscle are similar to those of other visceral muscles. The detrusor muscle is composed of an integrated unit of interconnected smooth muscle bundles including on the ventral face of the bladder a large longitudinal muscle, a dorsal sheet-like component of circular musculature, and a mesh structure on the lateral portion of the bladder. Collagen fibrils, microfilaments and small elastic fibers are positioned between muscle cells and beneath the epithelium and serosa.
Bladder dysfunction is caused by abnormal functioning of the bladder tissue, resulting in symptoms such as dysuria, frequency and urgency, incontinence, enuresis or complete loss of function. Dysuria is a form of bladder dysfunction associated with pain or burning sensation during urination and urinary frequency. It often leads to a sense of bladder fullness resulting in frequent urination and can be caused by infection, radiation, chemicals, foreign bodies, (catheters and stones), and infiltration of the muscles by tumors of the bladder or from adjacent organs. Incontinence which is the inability to retain urine in the bladder can result from neurological or mechanical disorders of the system that controls normal micturition such as detrusor instability, stress incontinence and mechanical incontinence. Detrusor instability is a condition in which the bladder undergoes frequent and uncontrollable contractions that cause incontinence as a result of damaged neural pathways. Enuresis is an involuntary passage or urine at night or during sleep.
Bladder dysfunction such as incontinence is a major source of morbidity among the elderly, affecting more than 10 million Americans. Management of urinary incontinence accounts for more that 15% of nursing home budgets as a cost of 8 billion dollars annually.
A variety of diseases and injuries can contribute to or cause the development of bladder dysfunction. For example, benign prostatic hyperplasia (BPH), a common disorder occurring in adult men, often produces bladder outlet obstruction and bladder hypertrophy. The percentage of adult men with histological evidence of BPH increases every year after the fourth decade, such that 80% of men in their eighth decade have BPH.
Detrusor instability which is associated with uninhibited contraction of the bladder smooth muscle is a common cause of bladder dysfunction. Nearly two thirds of patients with bladder outlet obstruction have detrusor instability. Even after the removal of the obstruction detrusor instability persists in one-third of the patients. In addition to obstruction-induced forms, detrusor instability is associated with radiation cystitis, interstitial cystitis, bladder tumors, bladder stones, and is commonly found in elderly women who are otherwise free of obstruction of detrusor hypertrophy. A significant proportion of these patients do not respond to currently available pharmacologic agents or are unable to tolerate the side-effects of these medications.
The molecular pathophysiology of obstruction-induced bladder dysfunction is uncertain. Kitada et al., J. Urology, (1989); v, 141 p.166-169. However, in partial outlet obstruction produced in adult animals, the anatomical, histological, cellular and molecular changes impair both storage and emptying. In the early phase of the obstruction, smooth muscle hypertrophy permits an increase in detrusor contractility. As obstruction persists, increasing amounts of extracellular matrix proteins leads to a decreased compliance and decreased emptying. It is postulated that obstruction induces a phenotypic modulation in the smooth muscle cells which initially alters contractility of the cell, and then ultimately affects the expression of extracellular matrix proteins. Lin, VK, Muscle, Matrix, and Bladder Function, Plenum Press, New York, N.Y. (1995); p.65-74. In the hypertrophied bladder, the smooth muscle cells and the smooth muscle bundles are enlarged and collagen fibril bundles are larger and longer. The degree of hypertrophy is apparently similar in all smooth muscle cells within a bundle and can be associated with detrusor instability. Mostwin et al., Muscle, Matrix, and Bladder Function, Plenum Press, New York, N.Y. (1995); p.21-28. In a guinea pig model, partial outlet obstruction produced by a jeweler's ring placed around the urethra of immature animals caused a slow obstruction without acute distension, ischemia and other lesions. The bladder responded with an increased smooth muscle mass attributed to muscular hyperplasia. The collagen content of the bladder was proportional to the muscle mass, and no significant decrease in nerves containing acetylcholine was observed. Levin et al., Muscle, Matrix, and Bladder Function, Plenum Press, New York, N.Y. (1995); p. 7-19. With increasing bladder weight, urodynamic abnormalities appeared, such as significantly higher voiding pressures, unstable contractions similar to those seen in humans, and loss of compliance. The maximum bladder weight gain, i.e. 3 fold greater than the control value, was associated with a loss of contractility and overflow incontinence. The velocity of muscle contraction decreased as the weight increased. Mostwin et al., Muscle, Matrix, and Bladder Function, Plenum Press, New York, N.Y. (1995); p.21-28. The decreased active force of hypertrophic bladder muscle correlated well with the decreased myosin concentration. An alternative explanation could be the altered metabolic supply of ATP. Uvelius, B et al., Muscle, Matrix, and Bladder Function, Plenum Press, New York, N.Y. (1995); p.29-39. The level of nerve growth factor (NGF) and the mRNA for NGF was higher in the obstructed bladder than in controls. Depletion of intracellular thapsigargin sensitive Ca.sup.++ stores blocks basal and stretch induced NGF production by cultured bladder smooth muscle cells. Protein kinase C (PKC) and tyrosine kinase also played an important role in stretch induced NGF production. Alterations in energetics, innervation, spontaneous contractile activity, and the accumulation of extracellular matrix proteins in hypertrophied bladder may contribute to an altered contractile force development and to the reduced ability of the bladder to empty. Muscle, Matrix, and Bladder Function, Plenum Press, New York, N.Y. (1995); p. 7-19, 29-40, 55-64.
Neurologic injury can also dramatically effect bladder function. In the United States 8,000 to 10,000 new cases of spinal cord injury are reported each year. Bladder dysfunction characterized by detrusor hyperreflexia and hypertrophy are common in patients with traumatic supra sacral spinal cord injury. These patients are typically incontinent, depending on the completeness of the lesion and the degree of external sphincter coordination. Maintaining continence in these patients can be difficult and often requires drastic procedures that decrease outlet resistance and completely suppress the bladder (external sphincterotomy with administration of anticholinergic agents) to preserve upper tract function. Many non-traumatic spinal cord diseases are also associated with detrusor hyperreflexia. These diseases include multiple sclerosis, amyotrophic lateral sclerosis, cervical spondylosis, epidural and meningeal tumors, syringomyelia, vascular malformations and radiation myelopathy. Detrusor hyperreflexia is also one of the most common consequences of cerebrovascular accidents, Parkinson's disease and Alzheimer's disease.
Nearly 50% of diabetics, which account for more than 2.5% of the American population, have some degree of bladder dysfunction. Bladder dysfunction in diabetics is caused by a variety of bladder abnormalities such as detrusor areflexia and detrusor hyperreflexia.
Significant bladder dysfunction can also occur as a result of pelvic plexus injury or abdomino-perineal resections. In these conditions, the bladder is characterized by hypocontractility and poor compliance due to a combination of sympathetic and parasympathetic injuries.
Children with congenital urethral obstruction have significant bladder dysfunction, contributing to urinary incontinence. The bladder abnormalities associated with bladder dysfunction in these children include detrusor instability, myogenic failure and poor bladder compliance. Bladder dysfunction often persists in these patients even after successful relief of the primary obstruction. Preservation of upper tract function depends on successful treatment of the bladder dysfunction.
Several therapies have been developed and are currently being used to treat bladder dysfunction. Therapies for detrusor instability include treatment with anticholinergic agents alone or in combination with musculotropic relaxants and local anesthetics such as oxybutynin and flavoxate. A significant proportion of patients with detrusor instability, however, do not respond to these agents. Anticholinergic agents are also associated with several side effects, including dry mouth, blurred vision, drowsiness and constipation. Other therapeutics which are sometimes used to treat detrusor instability include prostaglandin inhibitors, tricylelic antidepressants, beta-adrenergic agonists and alpha-adrenergic antagonists. There are no pharmacologic agents currently used to treat detrusor hypertrophy. Surgical procedures, such as removal of detrusor obstruction and external sphincterotomy, are often necessary for the treatment of bladder dysfunction.
It would be desirable to have a therapy that could be administered systemically and that could avoid the foregoing drawbacks.